Neuronal death in newborn striatum after hypoxia-ischemia is necrosis and evolves with oxidative stress

The mechanisms for neurodegeneration after hypoxia-ischemia (HI) in newborn s are not understood. We tested the hypothesis that striatal neuron death i s necrosis and evolves with oxidative stress and selective organelle damage . Piglets (similar to 1 week old) were used in a model of hypoxia-asphyxia and survived for 3, 6, 12, or 24 h. Neuronal death was progressive over 3-2 4 h recovery, with similar to 80% of putaminal neurons dead at 24 h, Striat al DNA was digested randomly at 6-12 h, Ultrastructurally, dying neurons we re necrotic, Damage to the Golgi apparatus and rough endoplasmic reticulum occurred at 3-12 h, while most mitochondria appeared intact until 12 h. Mit ochondria showed early suppression of activity, then a transient burst of a ctivity at 6 h, followed by mitochondrial failure (determined by cytochrome c oxidase assay). Cytochrome c was depleted at 6 h after HI and thereafter . Damage to lysosomes occurred within 3-6 h, By 3 h recovery, glutathione l evels were reduced, and peroxynitrite-mediated oxidative damage to membrane proteins, determined by immunoblots for nitrotyrosine, occurred at 3-12 h, The Golgi apparatus and cytoskeleton were early targets for extensive tyro sine nitration. Striatal neurons also sustained hydroxyl radical damage to DNA and RNA within 6 h after HI. We conclude that early glutathione depleti on and oxidative stress between 3 and 6 h reperfusion promote damage to mem brane and cytoskeletal proteins, DNA and RNA, as well as damage to most org anelles, thereby causing neuronal necrosis in the striatum of newborns afte r HI. (C) 2000 Academic Press.